SPARC (secreted protein acidic & rich in cysteine) belongs to the matricellular class of secreted glycoproteins. Although structurally dissimilar, these proteins regulate interactions between cells & their extracellular matrix (ECM) & feature prominently in morphogenesis, development, injury, & repair. SPARC has been shown to i) inhibit the cell cycle; ii) disrupt cell adhesion; iii) inactivate cellular responses to certain growth factors; iv) regulate ECM & matrix metalloproteinase (MMP) production; v) bind to specific collagens; & vi) promote a rounded cell shape through dissolution of focal adhesions & reorganization of the actin cytoskeleton. SPARC- null mice are viable but exhibit phenotypic abnormalities associated with the eye, connective & adipose tissues, bone, & wound healing. Moreover, cells cultured from SPARC-null vs. wild-type tissues showed significantly accelerated cell cycles, diminished production of collagen & transforming growth factor b- 1, enhanced adhesion, &/or altered levels of cadherins & matricellular proteins. The expression of SPARC in remodeling tissues, as a consequence of normal development or response to injury, coupled with its multiple effects on vascular cells of the vessel wall, has been consistent with our proposal that SPARC subserves a fundamental role in vascular morphogenesis & cellular differentiation. In this renewal application on the role of SPARC in blood vessel growth, we test 4 hypotheses based on our current knowledge of SPARC structure & function: 1) Certain characteristics of SPARC-null mice are related to compromised angio- or vasculogenesis; 2) Mice lacking both SPARC & its homolog SC1 will exhibit exacerbated vascular & connective/adipose tissue phenotypes, due in part to the release of conserved, bioactive peptides by MMP-3; 3) A target for the counteradhesive activity of SPARC in endothelial cells is VE-cadherin & components of its signaling pathway; 4) SPARC is a significant regulator of several activities of vascular endothelial growth factor on endothelial cells. The proposed experiments will provide a more precise understanding of how vessels grow in the context of signals mediated by SPARC, a dynamic resident of the extracellular space.